Breast cancer is the most common malignancy in women worldwide. The HER family regulates the growth and development of normal mammary gland, and overexpression of HER2 is associated with breast cancer. Trastuzumab, having the trade name of Herceptin, is the first humanized monoclonal antibody medicament for use in treatment of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer. Although Herceptin has become a standard therapeutic regime for HER2 positive malignancies, 40% of patients remain non-responsive to this medicament. Moreover, drug resistance has occurred as a common severe problem in anti-HER2 therapeutic approach. Redundance of the growth factor and interference among the intracellular signal transduction pathways are believed to be the main reasons that facilitate the drug resistance in breast cancer patients. Pertuzumab, recently developed by Genentech Corporation (USA) together with Roche Corporation, is a novel anti-HER2 humanized antibody. Unlike Herceptin, Pertuzumab targets an antigen epitode which is located in the extracellular region II of the HER2 receptor. Results of clinical experimental studies showed that use of Pertuzumab alone produces a weak anti-tumor therapeutic effect. However, it has been studied to show that use of Pertuzumab in combination with Herceptin can more completely block HER signal tranduction due to complementation of their mechanisms of effect, resulting in more effective inhibition of growth of tumor cells.
Glycosylation modification of protein is a process whereby a specific polysaccharide chain is added onto the protein in endoplasmic reticulum to form an oligosaccharide chain. Glycosylation of protein is site specific, and also enzyme-directed. Depending on the mode of linkage to the protein moiety, glycosylation modification of protein can either be O-linked or N-linked, in which the conservative N-glycosylation site being Asn-X-Thr/Ser, wherein X is any amino acid other than Pro. There is a conservative N-linked glycosylation site Asn297 within the CH2 region in the Fe segment of the heavy chain of human IgG. The Fe polysaccharide chain is essential for optimal binding of an antibody to various receptors, effective elimination of pathogens by the antibody, as well as control of clinical properties of a therapeutic antibody. N-glycosylation modification of human IgG Fab may have an obvious promoting or inhibitory effect on the function of binding of an antibody to an antigen. Minor changes in the position where glycosylation modification occurs may produce a completely different effect on subsequent processing of polysaccharide chain and binding activity of an antibody to an antigen.
The present applicant previously obtained a fully human anti-human HER2 (Her-2/neu) monoclonal antibody GB235-019 by using fully human scFV phage library screening technology and genetic engineering recombination expression technology (reference can be made to the Chinese Patent Application No. 201410705404.0). The monoclonal antibody can reduce transfusion reaction and immunogenicity, increase drug safety, and presents a better pharmacokinetic profile. Moreover, GB235-019 can be used in combination with other HER2 positive tumor therapeutic agents to treat HER2 positive tumors.